Management of hemorrhoids: Reviewing the role of diosmin

Introduction

Hemorrhoids (engorged anal fibrovascular cushions) are the common causes of anal pathology, necessitating a visit to colon and rectal surgeons. The ancient evidence of hemorrhoids can be traced as far back to 1700 BC in the Egyptian papyrus which recounts the cases of symptomatic hemorrhoids being treated with acacia leave ointment. However, despite being a common condition diagnosed in clinical practice, its true prevalence is difficult to ascertain, since a significant proportion of hemorrhoid patients rely on self-treatment, remain asymptomatic, or are embarrassed to report it. Nevertheless, the limited statistical data available indicates these rates to vary from 4.4% to 36.4% in the general practice, with the peak prevalence being reported between 45- 65 years of age and subsequent decline thereafter; it is rare before the age of 20. Since constant and abnormal distension of anal cushions and weakening/fragmentation of the connective tissues supporting these vascular cushions are the chief factors driving the development of this pathology, its risk factors include elderly age, chronic straining, upright posture, increased intraabdominal pressure, pregnancy, obesity, higher socioeconomic status, Caucasian race, sedentary lifestyle, lack of dietary fibers, and chronic spinal cord injury. Majority of the hemorrhoids are amenable to medical management and do not require active intervention. Surgical interventions provide definitive cure, although are not preferred due to attendant complications. The following treatise discusses the etiopathogenesis, classification, clinical presentation and treatment options for hemorrhoids, with special emphasis on the role of flavonoids (especially diosmin) in the medical management, as an adjunct to surgery, and postoperatively after hemorrhoidectomy.^1-7Sanchez C, Chinn BT. Hemorrhoids. Clin Colon Rectal Surg. 2011;24:5-13.
Ganz RA. The Evaluation and Treatment of Hemorrhoids: A Guide for the Gastroenterologist. Clinical Gastroenterology and Hepatology. 2013;11:593- 603.
Nisar PJ, Scholefield JH. Managing haemorrhoids. BMJ. 2003;327:847-51.
Johanson JF, Sonnenberg A. The prevalence of hemorrhoids and chronic constipation. An epidemiologic study. Gastroenterology. 1990 Feb;98(2):380-6.
Riss S, Weiser FA, Schwameis K, et al. The prevalence of hemorrhoids in adults. Int J Colorectal Dis. 2012 Feb;27(2):215-20.
Scott D, Papa MZ, Sareli M, et al. Management of hemorrhoidal disease in patients with chronic spinal cord injury. Tech Coloproctol. 2002;6(1):19-22.
Vazquez JC. Constipation, haemorrhoids, and heartburn in pregnancy. Clin Evid (Online). 2008 Feb 20;2008.pii: 1411.  

Pathophysiology of hemorrhoids

Hemorrhoids are enlarged, inflamed, thrombosed or prolapsed fibrovascular anal cushions, usually noted in the right anterior and posterior wall and left lateral wall of the anal canal. They receive their blood supply from the superior, middle and inferior hemorrhoidal artery and are drained by the respective veins. These vessels form direct arteriovenous communications within the cushion, from which hemorrhoidal bleeding occurs. The vascular cushions also contain connective tissues derived from the internal anal sphincter and the longitudinal muscles, which support adherence of the cushions to internal anal sphincter. The normally functioning anal cushions perform the physiological functions of maintaining rectal continence, protecting sphincter mechanism during bowel movement, ensuring closure of external anal sphincter during increased intraabdominal pressure (for example, coughing and sneezing) and maintaining resting pressure of the anal verge. However, with advancing age, from as early as 2nd to 3rd decade of life, there is gradual degeneration of the connective tissue framework of these cushions resulting in progressive loss of their supportive function. Consequently the cushions slide downwards and prolapse with attendant rise in venous pressure, impaired venous return, venous engorgement, venous stasis, inflammation, erosion, bleeding, and thrombosis. Similarly, the shearing effects of hard stools on the connective tissue framework may weaken anchorage of the cushions to internal anal sphincter, thereby promoting their downward descent and abnormal venous engorgement. Overall, while the pathophysiology of hemorrhoid is not completely elucidated, it is established beyond doubt that development of hemorrhoidal disease is associated with abnormal venous dilatation, vascular thrombosis, degenerative process in the collagen fibers and fibroelastic tissues, and distortion and rupture of the anal subepithelial muscles. Additionally, the recent burgeoning research in this context has revealed the possible pathological role of the following phenomenon in abnormal enlargement of anal cushions: Severe inflammatory reactions involving the vascular wall and surrounding connective tissues; over-expression of matrix metalloproteinase (MMP) resulting in accelerated degradation of connective tissue; neovascularization and hypervascularization of anorectum; morphologically abnormal cushions featuring dilated thin-walled vessels and absent or nearly-flat sphincter like constriction; dysregulated vascular tone due to imbalance between endotheliumderived constricting and relaxing factors; higher than normal resting anal pressure.²Ganz RA. The Evaluation and Treatment of Hemorrhoids: A Guide for the Gastroenterologist. Clinical Gastroenterology and Hepatology. 2013;11:593- 603.  ^,3Nisar PJ, Scholefield JH. Managing haemorrhoids. BMJ. 2003;327:847-51.  ^,8Lohsiriwat V. Hemorrhoids: From basic pathophysiology to clinical management. World J Gastroenterol. 2012;18(17):2009-2017.  ^,9Aigner F, Bodner G, Gruber H, et al. The vascular nature of hemorrhoids. J Gastrointest Surg. 2006 Jul-Aug;10(7):1044-50.  

Classification of hemorrhoids

In contrast to the relatively insensate columnar epithelium lining the rectum, the anal canal is lined by sensitive squamous epithelium. The junctional point between the two is recognized as dentate line; this anatomical reference is used to classify hemorrhoids depending upon which treatment is tailored. Hemorrhoids originating above the dentate line are known as internal hemorrhoids and are lined by columnar epithelium (figure 1). On the other

hand, hemorrhoids developing below this line are lined with sensate squamous epithelium, and are known as external hemorrhoids (figure 1). The internal hemorrhoids are further classified, as per Goligher’s classification depending upon the degree of prolapse and reducibility, into four grades (table 1). However, there is no such classification for external hemorrhoids. Combined existence of both types is known as interoexternal hemorrhoids.⁸Lohsiriwat V. Hemorrhoids: From basic pathophysiology to clinical management. World J Gastroenterol. 2012;18(17):2009-2017.  ^,10-12Agbo SP. Surgical Management of Hemorrhoids. J Surg Tech Case Rep. 2011;3(2):68-75.
Halverson A. Hemorrhoids. Clin Colon Rectal Surg. 2007;20:77-85.
MacKay D. Hemorrhoids and Varicose Veins: A Review of Treatment Options. Altern Med Rev. 2001;6(2):126-140.  

Clinical presentation and diagnosis of hemorrhoids

The main symptoms of hemorrhoidal disease are bleeding (bright-red arterial blood) with or without bowel movements, swelling, discomfort and/or irritation/pruritus. Other complaints may include mucous discharge, feeling of a lump at anal verge/ feeling of incomplete evacuation, soiling, and difficulty maintaining the local hygiene. The previously acutely edematous or thrombosed external hemorrhoids may present as skin tags. Pain is generally not the presenting complaint; rather, it is painless rectal bleeding with defecation and discomfort which generally prompt a clinic visit. However, a subset of patients may present with acute pain, swelling and disability, especially when hemorrhoids become irreducible, circumferentially prolapsed, gangrenous, or incarcerated; this is known as hemorrhoid crisis and these patients seek relief on an emergent basis.^1-3Sanchez C, Chinn BT. Hemorrhoids. Clin Colon Rectal Surg. 2011;24:5-13.
Ganz RA. The Evaluation and Treatment of Hemorrhoids: A Guide for the Gastroenterologist. Clinical Gastroenterology and Hepatology. 2013;11:593- 603.
Nisar PJ, Scholefield JH. Managing haemorrhoids. BMJ. 2003;327:847-51.   ^,8Lohsiriwat V. Hemorrhoids: From basic pathophysiology to clinical management. World J Gastroenterol. 2012;18(17):2009-2017.   ^,10Agbo SP. Surgical Management of Hemorrhoids. J Surg Tech Case Rep. 2011;3(2):68-75.   ^,13Chen CW, Lai CW, Chang YJ, et al. Modified LigaSure hemorrhoidectomy for the treatment of hemorrhoidal crisis. Surgery Today. 2014;44(6):1056-1062.  

Since clinical symptomatology of hemorrhoids may mimic other gastrointestinal conditions, which may be life-threatening including anal fissure and abscess, fibrous anal polyp, anal skin tag, perianal hematoma, rectal prolapse, perianal condylomas, dermatitis, and rectal tumor, it becomes pertinent to rule out these conditions. In this regard, perianal inspection, digital rectal examination, and anoscopy may be particularly useful in excluding or arriving at the definite diagnosis of hemorrhoids. Furthermore, flexible sigmoidoscopy should be performed for bleeding hemorrhoids in patients < 50 years of age; and colonoscopy in all patients > 50 years of age with hemorrhoidal symptomatology, patients presenting with bleeding and anemia (regardless of their age), those with bleeding uncontrolled with medical therapy, those with family history of colorectal cancer, and those with additional symptoms of abdominal pain, bloating and diarrhea.⁸Lohsiriwat V. Hemorrhoids: From basic pathophysiology to clinical management. World J Gastroenterol. 2012;18(17):2009-2017.  ^,12MacKay D. Hemorrhoids and Varicose Veins: A Review of Treatment Options. Altern Med Rev. 2001;6(2):126-140.  ^,14Villalba H, Abbas MA. Hemorrhoids: Modern Remedies for an Ancient Disease. Perm J. 2007 Spring;11(2):74-76.  

Management of hemorrhoids

Hemorrhoidal symptoms range from temporary and mild to persistent and severe. Hemorrhoids do not warrant treatment unless symptomatic. Even when symptomatic, depending upon the severity of symptoms and grade of hemorrhoid, age of the patient, and the comorbidities, the treatment should be graduated from simple conservative treatment (bowel management with avoidance of constipation and hard stools) to medical therapy, in-office procedures and finally operating room procedures.>³Nisar PJ, Scholefield JH. Managing haemorrhoids. BMJ. 2003;327:847-51.  ^,11Halverson A. Hemorrhoids. Clin Colon Rectal Surg. 2007;20:77-85.  ^,14Villalba H, Abbas MA. Hemorrhoids: Modern Remedies for an Ancient Disease. Perm J. 2007 Spring;11(2):74-76.   With regards to medical treatment, creams and suppositories containing astringents, analgesics, and steroids can be used to relieve irritation and pain but the effects are shortlived. Sitz baths can be particularly helpful in patients with anal irritation.¹Sanchez C, Chinn BT. Hemorrhoids. Clin Colon Rectal Surg. 2011;24:5-13.  ^,10Agbo SP. Surgical Management of Hemorrhoids. J Surg Tech Case Rep. 2011;3(2):68-75.   It is noteworthy that phlebotonic agents (for example diosmin), which improve venous tone, stabilize capillary permeability and increase lymphatic drainage and hence improve the underlying hemorrhoidal pathology, may be especially beneficial in the management of hemorrhoids (including hemorrhoidal crisis) and augmenting the outcomes of hemorrhoidectomy. Furthermore, since these agents address the metabolic aspects of chronic venous insufficiency associated with hemorrhoids, they tend to reduce the recurrence risk as well, and therefore are of special significance in not only tiding over the acute hemorrhoidal crisis but delaying the surgical intervention at the patient’s/surgeon’s discretion.^15-17Redefining the protocol for managing hemorrhoids. Available at http://www.gastroendonews.com/download/SR125_WM.pdf. Accessed on 01/12/2014.
Perera N, Liolitsa D, Iype S, et al. Phlebotonics for haemorrhoids. Cochrane Database Syst Rev. 2012 Aug 15;8:CD004322.
Misra MC, Imlitemsu. Drug treatment of haemorrhoids. Drugs. 2005;65(11):1481-91.  

Although operative and nonoperative interventions offer definitive cure, the associated postoperative complications, including pain, bleeding and anal stricture, can serve as significant deterrents. However, improvisation in instrument technology and advent of new operative techniques has resulted in operative/

nonoperative interventions being safer with less protracted convalescence course. The nonoperative interventions, which are usually performed in an outpatient settings, are indicated for first- and second-degree hemorrhoids either at the outset of presentation or if conservative/medical therapy fails. The operating room procedures, on the other hand, are reserved for third- and fourth-degree hemorrhoids, and those unresponsive to nonoperative interventions. Refer to table 2 for various nonoperative and operative interventions for hemorrhoid management.³Nisar PJ, Scholefield JH. Managing haemorrhoids. BMJ. 2003;327:847-51.  ^,10Agbo SP. Surgical Management of Hemorrhoids. J Surg Tech Case Rep. 2011;3(2):68-75.  ^,12MacKay D. Hemorrhoids and Varicose Veins: A Review of Treatment Options. Altern Med Rev. 2001;6(2):126-140.  

Therapeutic role of diosmin in the management of hemorrhoids

Introduced as a therapeutic agent in 1969, diosmin is a naturally-occurring flavonoid (a three-ringed molecule with OH groups attached) that can be obtained from various plant sources or extracted from another flavonoid, hesperidin. Its vasculoprotective (antiinflammatory and free-radical scavenging) properties and phlebotonic properties have been used clinically for more than 30 years in the management variceal dilatations, such as hemorrhoids. Additionally, it is indicated in the management of chronic venous insufficiency, lymphedema, and varicose veins as well. Table 3 summarizes the pharmacologic and pharmacokinetic properties of diosmin.¹⁸No authors listed. Monograph. Diosmin. Altern Med Rev. 2004;9(3):308-11.  ^,19Milano G, Leone S, Fucile C, et al. Uncommon serum creatine phosphokinase and lactic dehydrogenase increase during diosmin therapy: two case reports. Journal of Medical Case Reports. 2014;8:194.  

The mechanisms of action of diosmin remain incompletely deciphered. However, the putative mechanisms of benefits proposed include (depicted in the figure 2) inhibition of noradrenaline degradation by catechol-O-methyltransferase (COMT) resulting in improved venous tone; inhibition of leukocyte adhesion and activation which reduces inflammation; inhibition of platelet function; and improved lymphatic drainage. Nevertheless, inspite of as-yet unclear mechanisms of action, there is incontrovertible evidence of its efficacy and safety in the pre- and post-surgical management of hemorrhoids, including hemorrhoidal crisis.¹⁶Perera N, Liolitsa D, Iype S, et al. Phlebotonics for haemorrhoids. Cochrane Database Syst Rev. 2012 Aug 15;8:CD004322.  ^,20Gohel MS, Davies AH. Pharmacological agents in the treatment of venous disease: an update of the available evidence. Curr Vasc Pharmacol. 2009 Jul;7(3):303-8.   Furthermore, availability of its micronized form, which increases its bioavailability, has led to further improvement in its efficacy (figure 3, page 15). It is therefore suggested that natural yet synthesized, standardized, purified, and micronized diosmin without any impurities such as hesperidin (hesperidin is associated with unwanted side-effects) can be beneficial in reducing the grade of hemorrhoids and consequently the urgency and even the necessity for surgical interventions. Supporting this supposition, it has been shown that the micronized purified flavonoids (such as diosmin) decrease venous capacitance, venous distensibility, and venous emptying time in patients with chronic venous insufficiency. Overall, micronized purified diosmin may be given both pre and post surgery to obtain symptom relief as well as demarcate the area of operation.²¹Garner RC, Garner JV, Gregory S, et al. Comparison of the absorption of micronized (Daflon 500 mg) and nonmicronized 14C-diosmin tablets after oral administration to healthy volunteers by accelerator mass spectrometry and liquid scintillation counting. J Pharm Sci. 2002 Jan;91(1):32-40.  ^,22Shoab SS, Porter JB, Scurr JH, et al. Effect of oral micronized purified flavonoid fraction treatment on leukocyte adhesion molecule expression in patients with chronic venous disease: A pilot study. J Vasc Surg. 2000;31:456-61.  

Efficacy and safety of diosmin in the management of hemorrhoids: Clinical review

The efficacy and safety of diosmin in the medical management of hemorrhoidal disease as well as to

delay surgical interventions and ameliorate postsurgical symptoms has been extensively evaluated and reviewed. Additionally, its safety and efficacy in pregnancy, which is a well-established risk for hemorrhoids and is one of the chief reasons for increased predisposition of females to hemorrhoids, has also been assessed.

As early as 1994, Godeberge23 documented that two-month micronized purified diosmin treatment

compared to placebo in patients with hemorrhoidal disease significantly reduced the frequency and severity of acute attacks. While 40% of the study patients receiving diosmin reported acute attack of mean 2.6-day duration with mean severity of 1.1 on a scale of 1-3, the respective values for the patients receiving placebo treatment were 70%, 4.6 days and 1.6. On the overall symptom score as well, diosmin compared to placebo significantly improved the scores from baseline; diosmin and placebo reduced baseline overall symptom scores from 6.6 to 1.1 and 6.1 to 4.0, respectively (figure 4).²³Godeberge P. Daflon 500 mg in the treatment of hemorrhoidal disease: a demonstrated efficacy in comparison with placebo. Angiology. 1994 Jun;45(6 Pt 2):574-8.   In the ensuing years, further evidences reaffirmed the unequivocal efficacy of micronized purified diosmin in the management of hemorrhoidal disease. Ho²⁴Ho YH, Tan M, Seow-Choen F. Micronized purified flavonidic fraction compared favorably with rubber band ligation and fiber alone in the management of bleeding hemoorrhoids: randomized controlled trial. Dis Colon Rectum. 2000 Jan;43(1):66-9   and colleagues showed that this medical treatment (along with dietary modifications) safely alleviated bleeding in patients with non-prolapsed hemorrhoids. The study patients were randomized to receive the bulking agent alone-ispaghula husk (group I), rubber band ligation plus bulking agent (group II) or micronized purified diosmin plus bulking agent (group III). Evidently, group III patients reported expeditious relief from hemorrhoidal bleeding compared to other groups; days taken to obtain relief from hemorrhoidal bleeding, group I 10.6±2.3 days, group II 5.6±1.1 days and group III 3.9±1.2 days (figure 5). The equivalent safety profile of all treatments was established by no reported incidence of complications or side-effects. A group of Italian investigators²⁵Diana G, Catanzaro M, Ferrara A, et al. Activity of purified diosmin in the treatment of hemorrhoids. Clin Ter. 2000;151(5):341-4.   similarly authenticated

the efficacy of purified diosmin in the treatment of hemorrhoids ranging between grade 1 to 4 by noting pain and bleeding reduction rates of 79% and 67%, respectively, in the first week of treatment and 98% and 86%, respectively, in the second week of treatment; figure 6. Excellent tolerability of the treatment further augmented its clinical use Subsequently, Jiang²⁶Jiang ZM, Cao JD. The impact of micronized purified flavonoid fraction on the treatment of acute haemorrhoidal episodes. Curr Med Res Opin. 2006 Jan;22(6):1141-7.   and colleagues reported 7-day micronized purified diosmin vs placebo treatment to safely and significantly alleviate pain, edema and bleeding in patients with acute hemorrhoidal disease. Based on the composite interpretation of the foregoing information, it can be correctly concluded that diosmin treatment, particularly micronized purified diosmin, is safe and effective in

the management of hemorrhoidal symptomatology, including the episodes of acute attacks during crisis. In the special context of hemorrhoidal crisis, this noninvasive medical treatment would not only effectively and safely ameliorate acute symptoms but would help in avoiding or delaying the definitive operative procedures to a time more convenient to the patient and the surgeon.^25   ,27Bohl JL, Saleeby RG, Herline AJ, et al. Acute Hemorrhoidal Crisis. Seminars in Colon and Rectal Surgery. 2007;18(3):197-201.   ^,28Di Pierro F, Spinelli G, Monsu G, et al. Clinical effectiveness of a highly standardized and bioavailable mixture of flavonoids and triterpenes in the management of acute hemorroidal crisis. Acta Biomed. 2011 Apr;82(1):35-40.  

Additionally, the efficacy of diosmin as an adjunctive to non-operative interventions, such as sclerotherapy, has also been assessed. In patients with isolated strangulated hemorrhoids, administration of micronized purified diosmin along with single largedose injection sclerotherapy was noted to resolve symptoms in the majority of the patients (92.85%), without inducing any side-effects.²⁹Deen KI. Outpatient treatment of isolated strangulated haemorrhoids with single dose injection sclerotherapy and oral Daflon. Eur J Surg. 1996 May;162(5):403-5.  

Micronized purified diosmin has also been shown to reduce postoperative bleeding, pain and consumption of analgesics after hemorrhoidectomy procedures.³⁰Mlakar B, Kosorok P. Flavonoids to reduce bleeding and pain after stapled hemorrhoidopexy: a randomized controlled trial. Wien Klin Wochenschr. 2005 Aug;117(15-16):558-60.   A recent endeavor by Ba-bai-ke-re31 and colleagues revealed that administration of micronized purified diosmin fraction vs placebo in patients who underwent Milligan-Morgan open hemorrhoidectomy improved postoperative symptoms and resulted in shorter duration of hospital stay. A cohort of 86 patients with grade III-IV acute mixed hemorrhoids who underwent hemorrhoidectomy were randomized to receive either diosmin or placebo after surgery. Remarkably, patients on micronized purified diosmin defecated earlier, had more frequent bowel actions in the first postoperative week and had a shorter hospital

stay (table 4). Furthermore, postoperative symptoms were better controlled on diosmin vs placebo (table 5).³¹Ba-bai-ke-re MM, Huang HG, Re WN, et al. How we can improve patients’ comfort after Milligan-Morgan open haemorrhoidectomy. World J Gastroenterol. 2011 Mar 21;17(11):1448-56.  

Apart from the general population, the efficacy and safety of diosmin has also been documented in pregnant and post-puerperal women as well, who are at heightened risk of hemorrhoidal disease. Validating this assertion, intention-to-treat analysis of pregnant women with acute hemorrhoidal symptoms who received micronized purified diosmin for a median duration of 8 weeks before delivery and 4 weeks after delivery revealed 66% of them to obtain relief by the 4th day of treatment. The safety of treatment was established by no adverse pregnancy and fetal outcomes and no negative impact on infant growth and feeding.³²Buckshee K, Takkar D, Aggarwal N. Micronized flavonoid therapy in internal hemorrhoids of pregnancy. IntJ Gynaecol Obstet. 1997 May;57(2):145-5 1.  

Conclusion

Hemorrhoids are engorged anal fibrovascular cushions that develop due to constant and abnormal distension of anal cushions and weakening/fragmentation of the connective tissues which support these vascular cushions. Although most patients with hemorrhoids experience only mild symptoms or remain asymptomatic, a subset of them may develop prolapse, rectal bleeding, swelling, discomfort, irritation/pruritus and even acute pain, necessitating an intervention in the form of medical, nonoperative or operative procedure. However, conservative and medical therapy is generally preferred by patients.

Diosmin is a naturally-occurring flavonoid agent, which has proven efficacy and safety in the management of symptomatic hemorrhoids. Furthermore, availability of its micronized form, which increases its bioavailability, has led to further improvement in its efficacy. It is therefore suggested that the micronized purified form of diosmin can be

beneficial in reducing the grade of hemorrhoids and consequently the urgency and even the necessity for surgical intervention. In fact, it has been revealed that it is safe and effective in alleviating the hemorrhoidal symptomatology, including acute crisis. Additionally, its beneficial effects in ameliorating postoperative symptoms in patients who undergo hemorrhoidectomy have also been documented. Furthermore, its safe and efficacious use during pregnancy suggests the wide spectrum of population that can benefit from this medical therapy.

References

1. Sanchez C, Chinn BT. Hemorrhoids. Clin Colon Rectal Surg. 2011;24:5-13.
2. Ganz RA. The Evaluation and Treatment of Hemorrhoids: A Guide for the Gastroenterologist. Clinical Gastroenterology and Hepatology. 2013;11:593- 603.
3. Nisar PJ, Scholefield JH. Managing haemorrhoids. BMJ. 2003;327:847-51.
4. Johanson JF, Sonnenberg A. The prevalence of hemorrhoids and chronic constipation. An epidemiologic study. Gastroenterology. 1990 Feb;98(2):380-6.
5. Riss S, Weiser FA, Schwameis K, et al. The prevalence of hemorrhoids in adults. Int J Colorectal Dis. 2012 Feb;27(2):215-20.
6. Scott D, Papa MZ, Sareli M, et al. Management of hemorrhoidal disease in patients with chronic spinal cord injury. Tech Coloproctol. 2002;6(1):19-22.
7. Vazquez JC. Constipation, haemorrhoids, and heartburn in pregnancy. Clin Evid (Online). 2008 Feb 20;2008.pii: 1411.
8. Lohsiriwat V. Hemorrhoids: From basic pathophysiology to clinical management. World J Gastroenterol. 2012;18(17):2009-2017.
9. Aigner F, Bodner G, Gruber H, et al. The vascular nature of hemorrhoids. J Gastrointest Surg. 2006 Jul-Aug;10(7):1044-50.
10. Agbo SP. Surgical Management of Hemorrhoids. J Surg Tech Case Rep. 2011;3(2):68-75.
11. Halverson A. Hemorrhoids. Clin Colon Rectal Surg. 2007;20:77-85.
12. MacKay D. Hemorrhoids and Varicose Veins: A Review of Treatment Options. Altern Med Rev. 2001;6(2):126-140.
13. Chen CW, Lai CW, Chang YJ, et al. Modified LigaSure hemorrhoidectomy for the treatment of hemorrhoidal crisis. Surgery Today. 2014;44(6):1056-1062.
14. Villalba H, Abbas MA. Hemorrhoids: Modern Remedies for an Ancient Disease. Perm J. 2007 Spring;11(2):74-76.
15. Redefining the protocol for managing hemorrhoids. Available at http://www.gastroendonews.com/download/SR125_WM.pdf. Accessed on 01/12/2014.
16. Perera N, Liolitsa D, Iype S, et al. Phlebotonics for haemorrhoids. Cochrane Database Syst Rev. 2012 Aug 15;8:CD004322.
17. Misra MC, Imlitemsu. Drug treatment of haemorrhoids. Drugs. 2005;65(11):1481-91.
18. No authors listed. Monograph. Diosmin. Altern Med Rev. 2004;9(3):308-11.
19. Milano G, Leone S, Fucile C, et al. Uncommon serum creatine phosphokinase and lactic dehydrogenase increase during diosmin therapy: two case reports. Journal of Medical Case Reports. 2014;8:194.
20. Gohel MS, Davies AH. Pharmacological agents in the treatment of venous disease: an update of the available evidence. Curr Vasc Pharmacol. 2009 Jul;7(3):303-8.
21. Garner RC, Garner JV, Gregory S, et al. Comparison of the absorption of micronized (Daflon 500 mg) and nonmicronized 14C-diosmin tablets after oral administration to healthy volunteers by accelerator mass spectrometry and liquid scintillation counting. J Pharm Sci. 2002 Jan;91(1):32-40.
22. Shoab SS, Porter JB, Scurr JH, et al. Effect of oral micronized purified flavonoid fraction treatment on leukocyte adhesion molecule expression in patients with chronic venous disease: A pilot study. J Vasc Surg. 2000;31:456-61.
23. Godeberge P. Daflon 500 mg in the treatment of hemorrhoidal disease: a demonstrated efficacy in comparison with placebo. Angiology. 1994 Jun;45(6 Pt 2):574-8.
24. Ho YH, Tan M, Seow-Choen F. Micronized purified flavonidic fraction compared favorably with rubber band ligation and fiber alone in the management of bleeding hemorrhoids: randomized controlled trial. Dis Colon Rectum. 2000 Jan;43(1):66-9.
25. Diana G, Catanzaro M, Ferrara A, et al. Activity of purified diosmin in the treatment of hemorrhoids. Clin Ter. 2000;151(5):341-4.
26. Jiang ZM, Cao JD. The impact of micronized purified flavonoid fraction on the treatment of acute haemorrhoidal episodes. Curr Med Res Opin. 2006 Jan;22(6):1141-7.
27. Bohl JL, Saleeby RG, Herline AJ, et al. Acute Hemorrhoidal Crisis. Seminars in Colon and Rectal Surgery. 2007;18(3):197-201.
28. Di Pierro F, Spinelli G, Monsu G, et al. Clinical effectiveness of a highly standardized and bioavailable mixture of flavonoids and triterpenes in the management of acute hemorroidal crisis. Acta Biomed. 2011 Apr;82(1):35-40.
29. Deen KI. Outpatient treatment of isolated strangulated haemorrhoids with single dose injection sclerotherapy and oral Daflon. Eur J Surg. 1996 May;162(5):403-5.
30. Mlakar B, Kosorok P. Flavonoids to reduce bleeding and pain after stapled hemorrhoidopexy: a randomized controlled trial. Wien Klin Wochenschr. 2005 Aug;117(15-16):558-60.
31. Ba-bai-ke-re MM, Huang HG, Re WN, et al. How we can improve patients’ comfort after Milligan-Morgan open haemorrhoidectomy. World J Gastroenterol. 2011 Mar 21;17(11):1448-56.
32. Buckshee K, Takkar D, Aggarwal N. Micronized flavonoid therapy in internal hemorrhoids of pregnancy. IntJ Gynaecol Obstet. 1997 May;57(2):145-5 1.